The functional basis of immunoreactions is complex and is based on the well-regulated interaction between local and system-effective cellular and humoral elements of nonspecific defense and the system of specific defense by activated cells of the lymphopoetic system and the mediators and antibodies produced by them.
Depending on the type of stimulation the predominant defense activities can substantially vary.
This augmentation of systemic defense is brought about in a natural way during an infection event or, is produced artificially, such as by drug therapy. This is effected both systematically as well as locally through the respiratory, digestive and urogenital mucosas.
The organism naturally immediately reacts to an infection. The quality and extent of the immediate reaction depends on the type of antigen and the place of invasion. In principle, equal reactions will proceed when giving vaccines or other exogenic substances. A specific defense that is measurable e.g. by the detection of specific antibodies, will become effective only after a few days. After eliminating the triggering cause, the production of specific antibodies will decline and finally will cease. After the biological degradation of antibodies only the presence of specific “memory cells” indicates which antigens the organism had to put up with in the past. Under certain circumstances, particularly in the case of causes which can mostly no longer be determined, the organism reacts hyperactively to endogenic structures. The developing autoimmune reaction results in a continuous destruction of the endogenic tissue the decomposition products of which, in turn, stimulate the immune system. If this pathological regulating cycle is not interrupted the consequences will be finally fatal, at least for the tissue that is involved.
Diseases of an immunopathological genesis or participation are frequently encountered. Due to their chronic course and the difficulties to treat them they strongly affect the quality of the lives of the people involved and cause enormous losses to the economy. One of the autoimmune diseases occurring most frequently is rheumatoid arthritis from which about 1% of the people suffer. This disease manifests itself at about the age of 40. After 10 years approx. 50% of the patients are incapable of earning their livelihood, and 10%-20% of those are most seriously disabled. The results of treatment achieved so far by immunosuppression and supporting therapies are insufficient and frequently end with stopping of the therapy. After 3 years maximally only 50% of the patients treated initially with basic therapeutical agents are still under effective medication.
Due to the frequent insufficient efficacy and large scale side effects of the traditional suppressive therapy, the search continues for new therapeutical methods for treating autoimmune diseases. (J. Sany: Early Approaches To Immunotherapy of Rheumatoid Arthritis. Eur-J-Rheumatol-Inflam: 11 (1991), 139 û 147).
The aim of these therapies is to affect humoral and cellular immune mechanisms as well as mediator systems. Here, experimental attempts showed first successes in animal experiments and clinical testing. However, so far it was not possible to achieve a decisive breakthrough in prognosticating and effectively treating autoimmune diseases of patients.
Immunopathological participation plasma exchange and plasma sorption were successfully applied for a multitude of autoimmune diseases and diseases (R. T. Baldwin, R. R. Pierce and O. H. Frazier: Guillain-Barre Syndrome After Heart Transplantation. J-Heart-Lungtransplany.: 11 (1992), 817-819; J. Braun, J. Sieper, A. Schwarz, F. Keller, J. Heitz and H. V. Ameln: Severe Lupus Crisis With Agranu-locytosis and Anuric Renal Failure Due to a Mesangial Lesion (WHO IIB) û successful treatment with cyclophosphamide pulse followed by plasmapheresis (2). Br-J-Rheumatol: 30 (1991), 312-313; P. C. Dau: Plasmapheresis in Acute Multiple Sclerosis: Rationale and Results. J-Clin-Apheresis: 6 (1991), 200-204; H. H. Euler, J. O. Schroeder, R. A. Zeuner and E. Treske: A Randomized Trail of Plasmapheresis and Subsequent Pulse Cyclophosphamide in Severe Lupus: Design of the LPSG Trial. Int-J-Artif-Organs: 14 (1991), 639-646; D. C. Hess, K. Sethi and E. Awad: Thrombotic Thrombocytopenic Purpura in Systemic Lupus Erythematosus and Antiphospholipid Antibodies: Effective Treatment With Plasma Exchange and Immunosuppression. J-Rheumatol: 19 (1991), 1474-1478; R T. Korinthenberg and M. Sauer: The Gullian-Barre Syndrome in Childhood. Clinical Course and Therapeutic Measures. Monatsschr-Kinderheilkd: 140 (1992), 792-798).
Plasma exchange is one of the oldest therapeutic methods, with separated plasma (membrane plasmapheresis or centrifugation) being rejected and simultaneously substituted by donor plasma or human albumin. During a treatment the simple up to a double quantity of the plasma of a patient is exchanged. This method is not selective. To remove one or a few pathogenically important components, the entire plasma of the patient is exchanged and substances which are essential to the patient are rejected. This has serious consequences for the patient which are attempted to be treated by various substitution therapies. In addition, the danger arises of transmitting pathogens such as FIIV or the hepatitis pathogen.
In plasma sorption the initially separated plasma is directed through adsorber material. Substances bonding to certain plasma components are coupled to the absorber material, thus removing them from the patient s plasma. If plasma sorption is applied for removing immunologically important substances the method is referred to as immunoadsorption. Depending on the adsorber material used this method has a varying selectivity and specificity. Various ligands and carriers were clinically used for adsorbing immunoglobulin and immune complexes from the separated plasma.
Ligands clinically used in extracorporeal apheresis methods, include staphylococcal protein A, hydrophobic amino acids (tryptophan or phenylalanin), dextran sulfate, aggregated IgG, anti-human IgG, and antigens of blood groups.
Various autoimmune diseases were successfully treated extracorporeal apheresis immunoadsorption, including rapidly progressing glomerulonephretis, focal glomerulosclerosis, systemic lupus erythermatosus, antiphospholipid syndrome, vasculitides; e.g. periarteriitis nodosa, M. Wegener, rheumatoid arthritis, immunological thrombocytopenic purpura, inhibitors against coagulation factors, hyperimmunized or ABO-incompatible prospective transplantate recipients, polymyoisitis, neurological diseases; e.g. Guillain-Barre syndrome, polyneuropathy, amytrophic lateral sclerosis, myastenia gravis, multiple sclerosis.
Medicinal therapy has a number of disadvantages in treating auto immune diseases. Medicinal immunosuppression is non-selective and non-specific. Also new immunological therapies (monoclonal or polyclonal antibodies against activation markers, or receptor structures of immune cells and mediators) nonselectively suppress the immune response and/or induce immunity phenomena in the organism.
The disadvantages of all known apheresis/absorption systems, analogously to medicamentous immunosuppression, have a disadvantage due to their insufficient selectivity. This applies to the method of Balint and Hargreavans (U.S. Pat. No. 4.681.870), immobilizing staphylococcus aureus protein A on appropriate carriers. By this method IgG and IgG complexes are nonspecifically removed from the blood of patients. This refers also to the method of using carrier-coupled non-specific proteins, preferably immunoglobulins of various species, as immunoabsorbents of immune complexes described by Davis (WO 86/07152). By this method immune complexes, yet not the reactive individual components that are constantly newly formed in the case of autoimmune diseases, are eliminated.
Liberti and Pollora (U.S. Pat. No. 4.551.435) describe a method for the elimination of substances and immune complexes from blood by adding specific antibodies of a specific concentration to patient s blood and forming immune complexes with the substance to be eliminated. They are eliminated from the blood by factors such as C1q, rheumatoid factors, Fc receptors, and cells bearing Fc receptors immobilized on a solid carrier. The application of this method presupposes the cause to be known which, however, is not the case in most cases of autoimmune diseases and the causing antigen is required to be available in a purified condition for the production of antibodies. The immune complexes themselves are nonspecifically removed, not through protein A but through biomolecules, which, due to physiological reasons, have a high affinity to immunoglobulins.
The pathophysiologically relevant immunostructures vary in individual automimmune diseases. There is a variation even between the immunity phenomena of one and the same disease. The use of the known apheresis systems does not only result in an elimination of the immunopathologically relevant but also of the physiological immunoglobulins which are, however, essential to endogenic defenses. The result is a general weakening of the immune system with the risk of septic complications.